What is the optimal treatment plan for a patient with Heart Failure with Preserved Ejection Fraction (HFpEF)?

Optimal Treatment for Heart Failure with Preserved Ejection Fraction (HFpEF)

Start an SGLT2 inhibitor (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) immediately as first-line disease-modifying therapy for all HFpEF patients, regardless of diabetes status. 1

First-Line Disease-Modifying Therapy

• SGLT2 inhibitors are the cornerstone of HFpEF treatment with Class 2a recommendation from the American College of Cardiology, showing significant reductions in heart failure hospitalizations and composite cardiovascular outcomes. 1
• Dapagliflozin reduced the composite endpoint of worsening heart failure and cardiovascular death by 18% (HR 0.82,95% CI 0.73-0.92) in the DELIVER trial. 1
• Empagliflozin reduced heart failure hospitalization or cardiovascular death by 21% (HR 0.79,95% CI 0.69-0.90) in EMPEROR-PRESERVED. 1
• Critical point: No pharmacological agent has convincingly demonstrated mortality reduction in HFpEF as a standalone outcome, but SGLT2 inhibitors provide the strongest evidence for reducing morbidity. 2, 1

Symptom Management with Diuretics

• Use loop diuretics at the lowest effective dose to achieve and maintain euvolemia (no edema, no orthopnea, no jugular venous distension). 2, 1
• Start with furosemide 20-40 mg daily, bumetanide 0.5-1.0 mg daily, or torasemide 5-10 mg daily. 2
• Train patients to self-adjust diuretic doses based on daily weight monitoring and symptoms to avoid both under-treatment of congestion and over-diuresis leading to hypotension and renal dysfunction. 2
• Excessive diuresis reduces cardiac output in HFpEF patients and can prevent optimal use of other therapies. 2

Additional Pharmacological Options for Selected Patients

Mineralocorticoid Receptor Antagonists (MRAs)

• Consider adding spironolactone 12.5-25 mg daily, particularly if LVEF is in the lower preserved range (40-50%), with Class 2b recommendation. 1
• Spironolactone reduced heart failure hospitalizations (HR 0.83,95% CI 0.69-0.99) in the TOPCAT trial but did not reduce mortality. 1
• Monitor potassium and renal function closely when using MRAs to minimize hyperkalemia risk. 1

Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)

• Sacubitril/valsartan may be considered specifically for women and patients with LVEF 45-57%, as these subgroups showed benefit in PARAGON-HF post-hoc analyses (Class 2b recommendation). 1
• The overall PARAGON-HF trial did not achieve statistical significance for the primary endpoint (rate ratio 0.87,95% CI 0.75-1.01, p=0.06). 1

ACE Inhibitors and ARBs

• ACE inhibitors or ARBs are reasonable for blood pressure control if needed beyond HF-specific medications, though they have not shown mortality benefit in HFpEF. 1
• Target blood pressure <130/80 mmHg using appropriate antihypertensive medications. 1
• The CHARM-Preserved trial with candesartan and I-Preserve trial with irbesartan showed no reduction in primary composite endpoints. 2

Management of Comorbidities

• Aggressively treat hypertension as it is present in >90% of HFpEF patients and is central to disease pathophysiology. 3, 4
• Control ventricular rate in atrial fibrillation using beta-blockers or rate-limiting calcium channel blockers (verapamil or diltiazem). 2
• Evaluate and treat myocardial ischemia as it contributes significantly to HFpEF pathophysiology. 2
• Optimize diabetes management with preference for SGLT2 inhibitors given their additional heart failure benefits. 1

Non-Pharmacological Interventions

• Prescribe supervised exercise training programs (Class 1 recommendation) involving 3 sessions per week for 1-8 months at 40-90% of exercise capacity, which improves aerobic capacity by 12-14% and quality of life. 1
• Implement multidisciplinary heart failure programs for all patients to improve outcomes. 1
• Recommend sodium restriction and fluid management based on volume status. 2

Critical Medications to Avoid

• Never use nondihydropyridine calcium channel blockers (diltiazem or verapamil) in HFpEF patients as they increase risk of heart failure worsening and hospitalization. 1
  • Exception: These agents may be used for ventricular rate control in atrial fibrillation or treatment of hypertension/ischemia, as their negative inotropic effects are less dangerous in HFpEF than HFrEF. 2
• Avoid nitrates as they are associated with a signal of harm in HFpEF. 1

Treatment Algorithm

Step 1: Initiate SGLT2 Inhibitor

• Start dapagliflozin 10 mg daily (if eGFR ≥30 mL/min/1.73m²) or empagliflozin 10 mg daily (if eGFR ≥60 mL/min/1.73m²). 1

Step 2: Optimize Volume Status

• Titrate loop diuretics to achieve euvolemia, then maintain with lowest effective dose. 2, 1

Step 3: Control Blood Pressure

• Target <130/80 mmHg using RAAS antagonists (ACE inhibitors or ARBs) as first-line agents. 1

Step 4: Consider Additional Agents Based on Patient Characteristics

• If LVEF 40-50%: Add spironolactone 12.5-25 mg daily. 1
• If female or LVEF 45-57%: Consider sacubitril/valsartan. 1
• If atrial fibrillation: Use beta-blockers or rate-limiting calcium channel blockers for rate control. 2

Step 5: Address Comorbidities

• Treat hypertension, diabetes, obesity, coronary disease, and atrial fibrillation aggressively. 1

Step 6: Implement Non-Pharmacological Measures

• Prescribe supervised exercise training and enroll in multidisciplinary HF program. 1

Monitoring Requirements

• Assess volume status, renal function, and electrolytes regularly, especially with MRA therapy. 1
• Monitor symptoms and functional capacity to guide treatment adjustments. 1
• Track daily weights and train patients to adjust diuretics accordingly. 2

Common Pitfalls to Avoid

• Do not treat HFpEF patients identically to those with reduced ejection fraction, as response to therapies differs significantly. 1
• Do not overlook comorbidity management, which significantly impacts outcomes in HFpEF. 1
• Avoid excessive diuresis leading to hypotension and renal dysfunction, which reduces cardiac output in HFpEF. 2
• Do not delay SGLT2 inhibitor initiation while waiting to optimize other therapies, as benefits occur within weeks. 1

Advanced Treatment Considerations

• Refer to advanced heart failure specialist team for patients with advanced HFpEF refractory to standard therapies. 1
• Cardiac transplantation can be considered in eligible patients with advanced HFpEF. 1